It is an object of the present invention to provide novel quinoxaline dione compounds which are useful in the treatment of diseases in mammals, including a human, and especially in the treatment of diseases which can be treated by antagonizing an excitatory amino acid of such mammals.
Another object of the present invention is to provide a method of treating diseases in mammals, including a human, responsive to the blockade of glutamic and aspartic acid receptors which comprises administering to a mammal in need thereof a compound of the invention.
A third object of the present invention is to provide novel pharmaceutical compositions for the treatment of diseases in mammals, including a human, responsive to the blockade of glutamic and aspartic acid receptors.
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA), the xcex1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer""s, and Huntington""s diseases.
The compounds of the present invention may also be useful in the treatment of schizophrenia, Parkinsonism, epilepsy, anxiety, pain, and drug addiction.
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula 
or a pharmaceutically acceptable salt thereof wherein
R is hydrogen or hydroxy;
R1 is hydrogen,
alkyl,
arylalkyl,
(CH2)nOH, or
(CH2)nNR7R8;
R5 and R6 are each independently
hydrogen,
halogen,
NO2,
CN,
CF3,
SO2NR7R8,
PO3R9R10,
alkyl,
alkenyl,
alkynyl,
(CH2)nCONR7R8,
(CH2)nCO2R10,
NHCOR11,
wherein R7 and R8 are each independently hydrogen or alkyl or together R7 and R8 form a ring of from three to seven atoms,
R9 is hydrogen or alkyl,
R10 is hydrogen or alkyl,
R11 is hydrogen or alkyl, and
n is an integer of from zero to four;
A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b, and formed by the following bivalent radicals:
a-NR12xe2x80x94CHR13xe2x80x94CHR14-b,
a-CHR13xe2x80x94CHR14xe2x80x94NR12-b,
a-CHR13xe2x80x94NR12xe2x80x94CHR14-b,
a-CHR14xe2x80x94CH2xe2x80x94NR12xe2x80x94CHR13-b,
a-CHR13xe2x80x94NR12xe2x80x94CH2xe2x80x94CHR14-b,
a-CH2xe2x80x94CH2xe2x80x94CHR13xe2x80x94NR12-b,
a-NR12xe2x80x94CHR13xe2x80x94CH2xe2x80x94CH2-b,
a-CH2xe2x80x94CH2xe2x80x94NR12xe2x80x94CH2xe2x80x94CH2-b,
a-CH2xe2x80x94CH2CH2xe2x80x94NR12xe2x80x94CH2-b,
a-CH2 NR12xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2-b,
a-CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR12-b,
a-NR12xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2-b,
wherein
R12 is hydrogen, CH2CH2OH, or alkyl, and R13 and R14 are each independently hydrogen, CN, CONH2, CH2NH2, CH2OH, alkyl, arylalkyl, alkenyl, or CO2R15 wherein R15 is hydrogen or alkyl;
and a compound as above having the formula 
wherein R, R12, R5, and R6 have the meanings set forth above;
and a compound as above having the formula 
wherein R, R12, R5, and R6 have the meanings set forth above;
and a compound as above having the formula 
wherein R, R12, R5, and R6 have the meanings set forth above;
and a compound as above having the formula 
wherein R, R12, R5, and R6 have the meanings set forth above;
and a compound as above having the formula 
wherein R, R12, R5, and R6 have the meanings set forth above;
and further a compound as any above wherein R5 and R6 independently are
hydrogen,
halogen,
NO2,
CN,
SO2NR7R8 
wherein R7 and R8 independently are hydrogen or C1-3-alkyl which may be straight or branched or cyclic, and wherein R12 is C1-3-alkyl which may be straight or branched or cyclic;
and a compound having the formula 
wherein R12 is hydrogen, methyl, or ethyl and R6 is
NO2, SO2NMe2, 
xe2x80x83or 
and a compound having the formula 
wherein R12 is hydrogen, methyl, or ethyl and R6 is
NO2, SO2NMe2, 
xe2x80x83or 
and further method of treating disorders of a mammal, including a human, responsive to the blockade of glutamic and aspartic acid receptors, which comprises administering to a patient in need thereof an effective amount of a compound as any above in unit dosage form;
and a method as above wherein cerebrovascular disorders are treated;
and further a pharmaceutical composition comprising a therapeutically effective amount of a compound as any above together with a pharmaceutically acceptable carrier.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, oxalate, and the acetate.
Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine, and bromine are preferred groups.
Alkyl means a straight chained or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Alkenyl means a straight chained or branched chain alkenyl group of two to six carbon atoms or a cyclic alkenyl group of three to seven carbon atoms, for example, but not limited to ethylene, 1,2- or 2,3-propylene, 1,2-, 2,3-, or 3,4-butylene, cyclopentene, or cyclohexene.
Alkynyl means a straight chained or branched chain alkynyl group of two to six carbon atoms, for example, but not limited to ethynyl, 2,3-propynyl, 2,3- or 3,4-butynyl.
Aryl means a monocyclic or bicyclic carbocyclic aromatic ring system, for example, but not limited to phenyl, 2-naphthyl, or 1-naphthyl.
Arylalkyl means aryl as defined above and alkyl as defined above, for example, but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; a preferred group is benzyl.
Also included in the instant invention is a process for preparing a compound of formula (see Scheme I).
The process comprises
(1) reacting a compound of Formula I (Scheme I) with a brominating agent, for example, bromine in trifluoroacetic acid, bromine in acetic acid or mixtures thereof, or reacting a compound of Formula I with a chlorinating agent, for example, sodium hypochlorite in hydrochloric acid to give a compound of Formula II 
xe2x80x83wherein X is bromine or chlorine;
(2) treating a compound of Formula II above with fuming nitric acid in a solvent such as trifluoroacetic acid, acetic acid, or with mixtures thereof to give a compound of Formula III 
(3) deprotecting a compound of Formula III with under acidic or basic conditions to provide a compound of Formula IV 
(4) hydrogenating a compound of Formula IV in a solvent to give a compound of Formula V 
xe2x80x83wherein X may be hydrogen, bromine, or chlorine;
(5) reacting a compound of Formula V with oxalic acid in a solvent such as aqueous HCl or aqueous methanesulfonic acid or with diethyl oxylate to give a compound of Formula VI 
(6) reacting a compound of Formula VI wherein X is hydrogen sequentially with chlorosulfonic acid neat or in a solvent followed by treatment with a primary or secondary amine to give a compound of Formula VII 
xe2x80x83wherein R7 and R8 are as previously defined.
Also included in the invention is a process for the preparation of formula 
which comprises;
(1) reacting 3-nitrophthalic acid with a 1,3-dialkyl urea, neat or in a solvent to provide a compound of the formula 
(2) hydrogenating a compound of the above formula in a solvent to give a compound of the formula 
(3) reacting a compound of the above formula with a hydride reducing agent, for example, lithium aluminum hydride or the like in a solvent to give the compound of the formula 
(4) reacting a compound of the above formula with an acid chloride or acid anhydride, for example, acetyl chloride, ethyloxalyl chloride, acetic anhydride, or the like in a solvent to give a compound of the formula 
The compounds of the invention exhibit valuable biological properties because of their strong excitatory amino acid (EAA) antagonizing properties at the AMPA ((RS)-xcex1-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) binding site.
The compounds of the present invention exhibit binding affinity for the AMPA receptor as described by Honorxc3xa9 T, et al, Neuroscience Letters 1985;54:27-32 with IC50 values of  less than 100 xcexcM in this assay. Values for selected compounds are found in Table I.
To functionally measure AMPA antagonist activity, the effects of the excitatory amino acid antagonists on AMPA-induced neuronal degeneration in primary cortical neuronal cultures were examined using techniques similar to those outlined by Koh, et al. (J. Neurosci. 1990;10:693-705). When using a 100 xcexcM AMPA challenge, the claimed compounds generally had IC50 values  less than 30 xcexcM.
Also, compounds of the present invention when administered TV or IP in the in vivo AMPA seizure test, as described below, inhibit the clonic seizures induced by AMPA.
AMPA-Induced Clonic Seizures
AMPA given ICV (intracerebroventricular) (15 xcexcg/kg) to NMRI mice induces clonic seizures which should be inhibited by non-NMDA receptor antagonists.
Method
Test compound was given IV 5 minutes (or PO 30 minutes) before a 0.3 xcexcg ICV administration of AMPA to ten female NMRI mice (weighing 24-26 g) per dose. The number of mice experiencing clonic seizures within the next 5 minutes was noted. An ED50 value was calculated as the dose inhibiting 50% of the mice from having clonic seizures.
As a preliminary indicator of in vivo CNS activity, a maximal electroshock assay in CF-1 strain mice (20-25 g) is performed with corneal electrodes by conventional methods as described previously (Krall, et al., Epilepsia 1978;19:409-428). The claimed compounds generally demonstrated ED50 values of  less than 50 mg/kg.
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 10 mg of active ingredients or, more broadly, 0.1 to 100 mg per tablet, are accordingly suitable representative unit dosage forms.
Solid forms of pharmaceutical compositions for PO administration and injectable solutions are preferred.
The compounds of this invention are extremely useful in the treatment of central nervous system disorders related to their biological activity. The compounds of this invention may accordingly be administered to a subject, including a human, in need of treatment, alleviation, or elimination of an indication associated with the biological activity of the compounds. This includes especially excitatory amino-acid-dependent psychosis, excitatory amino-acid-dependent anoxia, excitatory amino-acid-dependent ischemia, excitatory amino-acid-dependent Parkinsonism, excitatory amino-acid-dependent convulsions, and excitatory amino-acid-dependent migraine. Suitable dosage ranges are 0.1 to 1000 mg daily, 10 to 500 mg daily, and especially 30 to 100 mg daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved, and the body weight of the subject involved, and further, the preference and experience of the physician or veterinarian in charge.
The following nonlimiting examples illustrate the present invention.